Process of preparing pyridyl carbinols and ketones

ABSTRACT

Process of preparing pyridyl carbinols and ketones by the reaction of a halopyridine, lithium and a carbonyl or nitrile compound in a one step procedure. The pyridyl carbinols and ketones are useful as intermediates for compounds having pharmacological activity, for example antihistamine or bronchodilator compounds.

United States Patent [191 Mendeison Aug. 28, 1973 PROCESS OF PREPARINGPYRIDYL CARBINOLS AND KETONES [75] Inventor: Wilford L. Mendelson,Philadelphia,

[73] Assignee: Smith Kline & French Laboratories,

Philadelphia, Pa.

[22] Filed: July 8, 1971 [21] App]. No.: 160,934

[52] US. Cl 260/297 R [51] Int. Cl C07d 31/32 [58] Field of Search260/297 R [56] References Cited OTHER PUBLICATIONS Klingsberg, Pyridineand its Derivatives, Part Two, in-

Primary Examiner-Alan L. Rotman Attorney-William H. Edgerton et al. v

[5 7] ABSTRACT Process of preparing pyridyl carbinols and ketones by thereaction of a halopyridine, lithium and a carbonyl or nitrile compoundin a one step procedure. The pyridyl carbinols and ketones are useful asintermediates for compounds having pharmacological activity, for exampleantihistamine or bronchodilator compounds.

6 Claims, No Drawings PROCESS OF PREPARING PYRIDYL CARBINOLS AND KETONESinvention relates to a process of preparing pyridyl carbinols andketones. The pyridyl carbinols and ketones prepared by the process ofthis invention are useful as intermediates for compounds havingpharmacological activity, for example antihistamine compounds such asphenyl-pyridyldialkylaminoalkanes and dialkylaminoalkyla-phenylpyridylmethyl ethers and bronchodilator compounds such ashydroxyphenyl-2- piperidinyl carbinols.

According to the process of this invention, pyridyl carbinols andketones are prepared by the reaction of a halopyridine, lithium and acarbonyl or nitrile compound in a one step procedure.

The process of this invention provides a good yield of product by aprocedure which is carried out in one step and is advantageous overproir art methods using pyridyl lithium or Grignard compounds.

By the prior art method of preparing pyridyl carbinols and ketones usingpyridyl lithium, two steps are required, the pyridyl lithium is firstprepared and then reacted with a carbonyl or nitrile compound. Accordingto the prior art, halopyridines do not react satisfactorily withmetallic lithium to form pyridyl lithium compounds. The Chemistry ofHeterocyclic Compounds, Pyridine and its Derivatives, Part Two,Klingsberg, Ed., lnterscience Publishers, lnc., 1961, pages 422-428. Bythe prior art method, pyridyl lithium compounds are prepared by thereaction of a halopyridine with an alkyl lithium compound, such asn-butyl lithium, at low temperature, i.e. at 45C. to 35C., and pyridylcarbinols and ketones are then prepared by reacting pyridyl lithium witha carbonyl or nitrile compound in a second step at about 40C. Wibaut etal., Recueil 70:1054 (1951). The process of this invention is animprovement in that it is carried out in one step and does not requirethe very low temperature of the prior art method.

Also, the process of this invention is advantageous over the prior artGrignard method of preparing pyridyl carbinols and ketones.Halopyridines do not readily form Grignard compounds and when formed,the reaction of the pyridyl magnesium halides to give carbinols andketones gives poor yields of the products. "The Chemistry ofHeterocyclic Compounds, Pyridine and its Derivatives," Part Two,Klingsberg, Ed., lnterscience Publishers, lnc., 1961, pages 437-439..

Pearce et al., A One-step Alternative to the Grignard Reaction, Chem.Comm, page 1160 (1970), have reported the reaction between organichalides, lithium and carbonyl compounds. Pearce et al. illustrate thisreaction with alkyl halides, bromobenzene and allyl bromide. All ofthese would react with magnesium to form stable Grignard compounds.Pearce et al. describe their process as a Grignard-type reaction.

Unexpectedly, it has now been found that halopyridines, whch do notreadily form Grignard compounds, react with lithium and a carbonyl ornitrile compound to form pyridyl carbinols and ketones.

Preferably, the carbonyl or nitrile compound used in the process of thisinvention is a benzaldehyde, phenyl ketone, benzoic acid ester, benzoicacid anhydride or benzonitrile, of which the phenyl groups areoptionally substituted. Preferably, the halopyridine used in the processof this invention is optionally substituted by a lower alkyl group.

The process of this invention is illustrated by the following reactionsequence:

x R- 'f 1 l Y .m/

in which:

is chloro, bromo or iodo, preferably chloro or bromo;

R is hydrogen, lower alkyl phenyl; R is lower alkyl; and

In the above compounds, the pyridyl ring is optionally substituted, forexample by lower alkyl, and the phenyl ring is optionally substituted bychloro, lower alkyl or lower alkoxy.

The process according to this invention is carried out by adding thehalopyridine and the carbonly or nitrile compound to two equivalents oflithium in a dry inert solvent such as an ether, for exampletetrahydrofuran or dimethoxyethane, preferably tetrahydrofuran. Thereaction is carried out at reduced temperature, for example at aboutl0C. to +SC., preferably at about 5C. to 0C., under an inert atmosphere,for example helium or, preferably, argon.

Hydroxyphenyl-Z-piperidinylcarbinols having bronchodilator activity areprepared by reacting a halopyridine, lithium and a loweralkoxy-benzaldehyde, oxidizing the resulting loweralkoxyphenyl-2-pyridyl carbinol to the corresponding ketone,dealkylating the lower alkoxy group or groups and reducing the ketone toa carbinol and the pyridyl to a piperidyl ring.

Alternatively, reacting a halopyridine, lithium and a lower alkoxysubstituted benzoic acid ester or anhydride or benzonitrile, thendealkylating the lower alkoxy group of the resulting lower alkoxyphenyl2-pyridyl ketone and reducing the ketone to a carbinol and the pyridylto a piperidyl ring gives hydroxyphenyl-Z- piperidinylcarbinols.

Antihistamine compounds are prepared from phenylpyridyl carbinols andketones by known procedures For example,dialykylaminoalkylaphenylpyridylmethyl ethers are prepared by condensinga phenyl-pyridyl carbinol, preferably as the sodio derivative, withdialkylaminoalkyl halide.

Phenyl-pyridyl-dialkylaminoalkanes, such as pheniramine orchloropheniramine, are prepared by reducing a phenyl-pyridyl carbinol orketone, for example using boron hydride/boron trifluoride, andalkylating the resulting benzylpyridine by treating with sodium amideand N,N-dimethyl-Z-chloroethylamine.

The following examples are not limiting but illustrate the process ofthis invention.

EXAMPLE l To 0.28 g. (0.04 m.) oflithium in 20 ml. of drytetrahydrofuran stirred at 5C. under helium, is added 2.5 g. (0.022 m.)of 2-chloropyridine and 2.7 g. (0.02 m.) of p-anisaidehyde. Theresulting mixture is stirred at 5C. for three hours, then is stirred atroom temperature for 1.5 hours.

The tetrahydrofuran is evaporated off, in vacuo, and ice water is addedto the residue, The mixture is extracted with ethyl acetate, the solventis removed from the extract in vacuo and the residue is slurried withether and filtered. The solid material is recrystallized from ethylacetatecyclohexane to give p-anisyl-2- pyridylcarbinol, m.p. l23l26C.

EXAMPLE 2 EXAMPLE 3 To 0.138 g. of lithium in .10 ml. of drytetrahydrofuran, stirred at 5C. to C. under helium, is added 1.78 g. of2-bromopyridine and 1.33 g. of p-anisonitrile in tetrahydrofuran. Theresulting mixture is stirred at 0C. for 2 hours and then allowed to warmto room temperature over 2 hours with stirring. The mixture is thenfiltered and concentrated in vacuo. The residue is slurried with ether.The ether is decanted from the resulting oily material. The oilymaterial is dissolved in 3N sulfuric acid. The mixture is stirred for 30minutes at room temperature, then cooled to 0C. Ammonium hydroxide isadded and the precipitate is filtered off to give p-anisyl-Z-pyridylketone.

EXAMPLE 4 By the procedure of Example 1 using, in place ofpanisaldehyde, the following:

benzalclehyde o-chlorobenzaldehyde p-chlorobenzaldehyde o-tolualdehyde 3,4-methylenedioxybenzaldehyde the products are. respectively:

phenyl-Lpyridylcarbinol o-chlorophenyl-Z-pyridylcarbinolp-chlorophenyl-Z-pyridylcarbinol o-tolyl-Z-pyridylcarbinol3,4-methylenedioxyphenyl-Z-pyridylcarbinol.

EXAMPLE 5 To 0.02 m. of lithium in dry ether, stirred at 0C. underargon, is added 0011 m. of 4-chloropyridine and 0.01 m. ofbenzaldehyde.The mixture is stirred at 0C.

- for 3 hours, then at room temperature for 2 hours.

The ether is evaporated off, in vacuo. Ice water is added and themixture is extracted with ethyl acetate. The extract is concentrated andthe residue is triturated with ether and filtered to give phenyl-4-pyridylcarbinol.

EXAMPLE 6 By the procedure of Example 3, using 2.86 g. of panisic acidanhydride in place of p-anisonitrile, panisyl-Zpyridyl ketone isobtained.

EXAMPLE 7 By the procedure of Example 3, using 1.50 g. of ethyi benzoatein place of p-anisonitrile, the products are phenyl-Z-pyridyl ketone andphenyl-bis-( 2- pyridyl)carbinol. The products are separated by standardprocedures such as fractional recrystallization or fractionaldistillation.

What is claimed is:

l. An'improved process of preparing pyridyl carbinols and ketones theimprovement which consists essentially of reacting in one step ahalopyridine, lithium and a carbonyl compound selected from abenzaldehyde, phenyl ketone, benzoic acid ester and benzoic acidanhydride in an ether solvent at about l0C. to +5c.

2". The process of claim 1 in which two equivalents of lithium are used.

3. The process of claim 1 in which the reaction is carried out intetrahydrofuran. 4

4. The process of claim 1 in which the carbonyl compound is a loweralkoxy-benzaldehyde.

5. The process of claim 1 which comprises reacting in one step2-chloropyridine, lithium and panisaldehyde to givep-anisyl-Z-pyridylcarbinol.

6. The process of claim 1 which comprises reacting in one step2-bromopyridine, lithium and panisaldehyde to givep-anisyl-Z-pyridylcarbinol.

zgz g g UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,755,341 Dated August 28 1.973

Invent r) Wilford L. Mendelson v It is certified that error appears inthe above-identified patent and that said Letters Patent are herebycorrected as shown below:

!" Column 1, 7 line 4, before "invention" insert 1 Column 2, line 11,before "is" insert X Column 2, line 19, after "lower alkyl" insert 01'."o

Column 2, line 31, carbonly should read carbonyl 7 Column 2, line 56,dialykylaminoalkyla-a should read dialkylaminoalkyl Ol- Signed andsealed this 5th day of March 197A.

(SEAL)' v Att est: 1

EDWARD M.FLETCHER,JR o. MARSHALL DANN Attesting Officer 7 Commissionerof Patents

2. The process of claim 1 in which two equivalents of lithium are used.
 3. The process of claim 1 in which the reaction is carried out in tetrahydrofuran.
 4. The process of claim 1 in which the carbonyl compound is a lower alkoxy-benzaldehyde.
 5. The process of claim 1 which comprises reacting in one step 2-chloropyridine, lithium and p-anisaldehyde to give p-anisyl-2-pyridylcarbinol.
 6. The process of claim 1 which comprises reacting in one step 2-bromopyridine, lithium and p-anisaldehyde to give p-anisyl-2-pyridylcarbinol. 